GINGIVAL OVERGROWTH: ROLE OF PHENYTOIN METABOLITES

牙龈过度生长：苯妥英代谢物的作用

• 批准号: 3220069
• 负责人: JAMES H MAGUIRE
• 金额: $ 9.19万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1986-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3220069
• 关键词: anticonvulsants; child (0-11); drug adverse effect; drug metabolism; fibroblasts; gingiva hyperplasia; human subject; phenytoin; stereochemistry; tissue /cell culture; urinalysis

It is estimated that four to five million epileptics in he United States are treated with 5, 5-diphenylhydantoin (PHT, phenytoin). Of this population, approximately two to three million individuals ("responders") develop gingival overgrowth as an undesirable effect of the drug. Studies in human and model mongrel cat populations have suggested that PHT metabolites may be responsible for development of the lesion by selecting for a subpopulation of synthetically hyperactive gingival fibroblasts, which proliferate in susceptible individuals. A population of pediatric patients on PHT therapy will be classified as responder or non-responder individuals on the basis of oral examinations. Urinary metabolites from such individuals will be quantitated by gas chromatography and high-pressure liquid chromatography (HPLC) to determine the state of conjugation, stereochemical composition, and relative amounts of phenolic (p-HPPH, 5-(4-hydroxyphenyl)-5phenylhydantoin) and dihydrodiol (DHD, 5-(3, 4-dihydroxy-1, 5-cyclohexadien-1-yl)-5-phenylhydantoin), and other minor metabolites of PHT. These data will be used to determine if metabolic differences exist between the human responder and non-responder groups. Gingival fibroblast cultures from responder, non-responder, and p-HPPH and DHD to determine what cytotoxic or mitogenic effects such compounds may possess. The mode of PHT metabolism by in vitro gingival firbroblast cultures will be examined and compared by use of HPLC techniques. The stereochemistry of urinary p-HPPH and DHD in responder and non-responder mongrel cats will be compared. The ability of racemic p-Hpph and its enantiomers to induce gingival overgrowth in responder mongrel cats will also be evaluated. Such studies will allow evaluation of potentially toxic arene oxide and other metabolic pathways in responder and non responder individuals, the biological activity of such metabolic products, and the sites (liver and/or gingivae) of production of the active metabolites. With the added insights into the biochemical mechanism of the induction of gingival overgrowth, it may be possible to develop screening procedures to identify potentially susceptible individuals. New theories for the design of less-toxic antepileptic drugs may also be developed.

据估计，美国有四到五百万癫痫患者 用5，5-二苯基乙内酰脲（PHT，苯妥英）处理。 本 人口，大约200万至300万人（“响应者”） 发展牙龈增生作为药物的不良影响。 研究 在人类和模型杂种猫群体中的研究表明， 代谢物可能是负责发展的病变， 对于合成活性过高的牙龈成纤维细胞亚群， 在易感个体中增殖。 一群儿童 接受PHT治疗的患者将被分类为应答者或非应答者 个人根据口头考试。 尿代谢产物来自 这些个体将通过气相色谱法定量， 高压液相色谱法（HPLC），以确定 共轭、立体化学组成和酚类化合物的相对量 （p-HPPH，5-（4-羟基苯基）-5-苯基乙内酰脲）和二氢二醇（DHD，5-（3， 4-二羟基-1，5-环己二烯-1-基）-5-苯基乙内酰脲）和其它次要的 PHT的代谢产物。 这些数据将用于确定代谢 人类响应者和无响应者群体之间存在差异。 来自应答者、非应答者和p-HPPH的牙龈成纤维细胞培养物， DHD，以确定这些化合物可能具有的细胞毒性或促有丝分裂作用 拥有. 牙龈成纤维细胞体外代谢苯妥英钠的模式 将使用HPLC技术检查和比较培养物。 的 应答者和非应答者尿p-HPPH和DHD立体化学 将比较杂种猫。 外消旋p-Hpph及其衍生物的 对映异构体诱导牙龈过度生长的反应杂种猫将 也被评价。 这些研究将允许评估潜在的毒性 应答者和非应答者的芳烃氧化物和其他代谢途径 个体，这种代谢产物的生物活性， 活性代谢物的产生部位（肝脏和/或牙龈）。 随着对诱导的生化机制的深入了解， 牙龈增生，这可能是可能的发展筛选程序， 识别潜在易感个体。 设计的新理论 毒性较小的抗癫痫药物也可能被开发出来。